Inherited platelet dysfunction and hematopoietic transcription factor mutations

Abstract

Transcription factors (TF) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for defects in platelet production, morphology, and function. The hematopoietic TFs implicated in patients with impaired platelet function include runt related transcription factor 1 (RUNX1), Fli-1 proto-oncogene, ETS transcription factor (FLI1), GATA-binding protein 1 (GATA1), and growth factor independent 1B transcriptional repressor (GFI1B). These TFs act in a combinatorial manner to bind sequence-specific DNA within a promoter region to regulate lineage-specific gene expression, either as activators or repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these transcription factors affect diverse aspects of megakaryocyte biology, and platelet production and function, culminating in thrombocytopenia, platelet dysfunction, and associated clinical features. Mutations in TFs may occur more frequently in patients with inherited platelet dysfunction than generally appreciated. This review focuses on the alterations in hematopoietic TFs in the pathobiology of inherited platelet dysfunction.

Transcription Factor GFI1B in Health and Disease

“…Consistent with the Gfi1b KO effect on megakaryopoiesis (20, 22, 23), different mutations in GFI1B are involved in platelet-related bleeding disorders (42). …”

Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features

“…3–10 In 2013, Stockley et al . used next-generation sequencing (NGS) to analyze 13 unrelated patients suspected of having an inherited qualitative platelet defect in the UK Genotyping and Phenotyping of Platelets (UK-GAPP) study.…”

Defective acid hydrolase secretion in RUNX1 haplodeficiency: Evidence for a global platelet secretory defect

“…Transcription factor RUNX1 plays a major role in hematopoiesis and megakaryopoiesis, and RUNX1 mutations are associated with familial thrombocytopenia, impaired platelet function and megakaryopoiesis, and a predisposition to acute myelogenous leukemia [1–3]. The mutation in most such patients is in the conserved DNA-binding RUNT domain [1, 2, 4].…”

“…A number of platelet abnormalities have been reported in patients with RUNX1 mutations, including a deficiency of granular content (storage pool deficiency, SPD) affecting dense granules (DG) and alpha granules, impaired aggregation, DG secretion, and protein phosphorylation [2–5]. In addition, abnormalities in mechanisms that regulate secretion have been reported in some patients [2, 3, 5], including in myosin light chain and pleckstrin phosphorylation, and decreased platelet PKC-θ [6, 7]. Platelet mRNA expression profiling of a patient with RUNX1 mutation [8] and other studies [7] have shown downregulation of several genes, including MYL9 , PRKQ ALOX12 and PF4, and some of these are direct transcriptional targets of RUNX1, providing evidence for aberrations in multiple platelets mechanisms, including in those regulating platelet responses to activation [2, 9–12].…”